Cardiac hypertrophy is one of the most important adaptive responses of the heart and plays a critical role in the onset of cardiac dysfunction during the transition to heart failure. Although the precise signaling pathways which orchestrate specific features of the in vivo hypertrophic response are unknown, a great deal of progress has been made toward the molecular dissection of the signaling pathways which might regulate in vitro hypertrophy in cultured neonatal rat heart cells. In the past five years, an experimental strategy has been designed to first identify candidate signaling molecules in a well-characterized cultured myocardial cell model system, followed by a rigorous assessment of the role of these molecules in an in vivo model system of hypertrophy in the adult mouse heart. Previous studies have established this mouse model as a valid system with fidelity to hypertrophy in larger mammalian species, including man. Miniaturized physiological technology has been coupled with transgenic and gene targeting strategies to exact cause-effect relationships between specific components in the pathway and the onset of defined molecular, morphological, and physiological features of hypertrophy. The central theme of our current Program is to critically evaluate the role of candidate signaling pathways in the activation of distinct features of in vivo cardiac hypertrophy and dilated cardiomyopathy in adult myocardium. Recent studies have defined a role for both gp130 and retinoid-dependent signaling pathways in the positive and negative control of the hypertrophic response in the in vitro assay system. Recently, cardiotrophin-1 and gp130 dependent pathways have been shown to promote cardiac myocyte survival (1) and to block cardiomyocyte apoptosis via MAP kinase dependent pathways (2). In addition, recent studies support an important role for both gp130 and retinoid signaling pathways in cardiac growth and/or hypertrophy in the in vivo contest. The major objective of this Project is to rigorously assess the role of gp130 and retinoid signaling pathways in the positive and negative regulation of distinct phenotypic features of in vivo cardiac hypertrophy, and subsequently to explore the role of these pathways in the activation of phenotypic feature of eccentric hypertrophy and dysfunction seen in the setting of dilated cardiomyopathy. The central approach will utilize a combination of miniaturized physiological technology and a variety of approaches to engineer gain and loss of function mutations in the adult mouse heart. The identification of a role for gp130 and RXRalpha in the activation or suppression (respectively) of hypertrophy in the setting of delated cardiomyopathy could ultimately lead to the identification of new molecular insights into the determinants that mediate the transition from cardiac hypertrophy to heart failure.